The invention relates to a wound dressing for the controlled release of active substances to wounds, especially of wound healing-promoting substances to slow-healing, chronic wounds, as well as a process for its manufacture.
By definition, every wound that shows no tendency to heal within eight weeks is to be regarded as chronic. In current wound therapy one has to take into account the following aspects of therapy with respect to wound dressings:
The wound dressing is to create a warm and moist wound environment while largely excluding atmospheric oxygen, as wounds heal more rapidly under occlusion. As the cause for the xe2x80x9chealingxe2x80x9d action of an occlusive milieu the following mechanism is, inter alia, being discussed in the literature: Due to the absence of oxygen, the wound is forced to convey oxygen to the wound area via the blood. This takes place through increased pannus formation under vascularisation and thereby promoted wound healing.
In order not to disturb the wound healing process, the wound dressing should be changed only rarely since removing a fully soaked wound dressing causes a loss of components of wound exudate and thus of immunocompetent cells.
Everything the endogenic defence and purification mechanisms cannot cope with must be removed from the wound. In particular, secretion which does not run off and is possibly infected with germs entails a high risk of infection. Possibly, this negative effect is even increased by an unsuitable dressing of poor absorbent power and water vapour permeability.
Wound dressings can be classified into various groups on the basis of their properties. The following dressings are being distinguished:
Interactive wound dressings: hydrocolloids, hydrogels, alginates, polyurethane foams and films.
Active wound dressings: activated charcoal compresses or pads, silver-activated charcoal compresses or pads and iodine gauze. Through absorptive processes, they actively influence the wound climate and have a physicochemically defined mechanism of action, but only negligible absorbent power for secretion.
If one classifies according to breathing capacity, then alginates, hydrocolloid gels, hydrogels and special films belong to the gas-permeable systems, and the hydrocolloid, hydrogel and flexbible foam compresses or pads as well as the standard films belong to the semipermeable/semi-occlusive systems.
Examinations have shown that, compared to acute wounds, chronic wounds contain considerably more leucocytes and matrix metalloproteinases (MMP). Through increased MMP concentration the extracellular matrix is degraded, and, in addition, growth factors, including their recipes, are degraded at the target cells, so that the wound healing cascade is halted. By external delivery of wound healing factors, especially of growth factors, it is possible to break the vicious circle, and the wound healing cascade can restart.
The use of gels, especially of hydrogels, for treating damaged skin and wounds is described in the literature. Their use is advantageous in that they possess good biological compatibility, especially when applied for a prolonged period of time. For the production of these hydrogels, various substances, auxiliary agents and active agents are used.
Gels can be used alone or together with active agents. For example, if gels are used as such, i.e. without active agent, they serve above all to regulate the wound environment. The aim is to create a wound environment which promotes the healing of the wound. This is based on the finding that wounds heal better and more quickly under warm and humid conditions.
Gels are also used as carriers for active agents. Here, a controlled release of active substance to the wound is aimed at. Active substances or active substance groups mentioned in this context are, for example: deoxyribonucleosides, growth factors (PDGF, TGF, FGF, CGF, CTAP), protein kinase C, antibiotics, antimycotics, enzyme inhibitors, antihistaminics, antiseptics, vitamins, glucocorticoids, antiviral active substances, steroids, insulin and analgesics.
DE 38 27 561 C describes the use of flexible, hydrophile, water-swellable gel films. For the production thereof, anion-active polymers are used together with cation-active polymers. In addition, humectants, water-dispersible auxiliary agents, up to 70% of water, and active substance are contained.
DE 44 46 380 A1 describes hydrogels, for example based on gelatine, for releasing therapeutic and/or cosmetic active substances to the skin, or for cosmetic care and treatment of sensitive sites of the skin and nails. The hydrogels described are characterized by the fact that they are rigid-elastic bodies adapted to the contours of sites of the human body. These hydrogels may be characterized by a pressure-sensitive adhesive surface.
WO 98/17252 describes a water-insoluble film-forming gel having (bio)adhesive properties for local delivery of pharmaceutical active agents. Said gel contains at least one water-insoluble cellulose derivative and a non-aqueous solvent. It may be applied to skin as well as to mucous membranes.
U.S. Pat. Nos. 5,770,228, 4,717,717 and WO 93/08825 describe gels based on hydroxyethyl cellulose. These gels are used for the release of growth factors, e.g. PDGF, TGF, EGF and FGF. In addition, gels may contain a preserving agent such as, for example, methyl parabene or ethanol.
U.S. Pat. Nos. 5,705,485 and 5,457,093 describes gels for treatment of wounds. These contain effective amounts of PDGF (Platelet Derived Growth Factor). As gel formers, cellulose derivatives are used, for instance carboxymethyl cellulose. Further contained are agents carrying a load opposite to that of the PDGF. Here, amino acids such as, for instance, lysin or alanine, are mentioned, but also metal ions such as magnesium or zinc.
U.S. Pat. No. 5,591,709 describes a gel as active substance delivery system. As gel-forming components, gelatine, agrose, collagen and hydrophile cellulose derivatives are used. The system. serves to release insulin, growth hormones and thyroxine or triiodothyronine.
U.S. Pat. No. 5,578,661 describes a gel suitable for delivery of PDGF. This is an aqueous mixture of at least three components capable of gel formation. They contain a hydrophile, water-soluble polymer as component 1: polyethylene glycol, poly-vinyl pyrrolidone; an acid-containing polymer as component 2: polyvinyl pyrrolidone-polyacrylic acid copolymer, polyacrylic acid, polymethyl vinyl ether-polymaleic acid anhydride copolymer, polyethylene maleic acid anhydride; a polymer having amino groups as component 3: e.g. poly-saccharides, poly-L-lysin. The acid functions of the second component lead to cross-linking and/or form hydrogen bridges together with the first component. Here, the third component serves to accept hydronium ions. The result is a cohesive hydrogel. It is a characteristic of this system that the gel does not form spontaneously but only with time. Consequently, it is possible to initially process a low-viscous mixture. This mixture, however, gradually cures and forms a hydrogel.
U.S. Pat. No. 5,427,778 describes a gel for the release of growth factors (EGF, FGF, PDGF, TGF, NGF and IGF). As gel-former, a polymer based on acrylamide is used.
It is a substantial drawback of the described systems that they are characterized by a considerably limited swelling capacity and that upon swelling they more or less loose their shape and coherence. For this reason, it is necessary to cleanse the wound thoroughly after application of the systems to the wounds. This cleansing may lead to irritation or disturbance of the healing process. Especially when hydrocolloids and hydropolymers are used, it is possible that, despite careful cleansing, gel particles are walled off in the wound, which will possibly cause a foreign body response. This can lead to considerable complications.
Starting from the above-discussed prior art, it was the object of the present invention to provide a wound dressing for controllable release of active substance and, in particular, of wound healing-promoting substances to slow healing, chronic wounds, as well as a process for its manufacture, which wound dressing is capable of absorbing liquid under increase in volume without loosing its coherence in the process, and which moreover substantially promotes the healing process.
To achieve this object in a wound dressing for the controllable release of active substances to a wound, especially of wound healing-promoting substances, it is proposed according to the invention that said wound dressing has a layered structure for the purpose of absorbing liquid, especially wound exudate, under volume increase, said structure at least comprising one polymer-containing layer, one woven fabric-like or nonwoven-like layer and at least one active agent, and that the polymer-containing layer contains hydrocolloid-containing swellable hydrogel as absorbent for liquid.
Advantageously, by means of the configuration of the wound dressing according to the invention, it is achieved that on the one hand said wound dressing is able to absorb liquid such as wound exudate in larger amounts under volume increase without loosing its coherence, and that on the other hand by means of said wound dressing, wound healing-promoting substances are delivered to the wound, thereby inducing an accelerated healing process, especially by providing the healing-promoting occlusion of the wound, said healing process making the frequent changing of the dressing superfluous.
The active substance-containing wound dressing advantageously contains hydrocolloid-containing hydrogels which, on account of their swelling capacity, are able to absorb liquid while maintaining their coherence. The colloid portion of the wound dressing gradually binds the exudate under transformation into a free gel which lines the wound and its recesses. In contrast thereto, the hydrogel forms a coherent matrix which has a swelling effect especially in dry wounds, and which dissolves coats as well as necroses.
The active substance-containing wound dressing according to the invention moreover serves to release growth factors to slow-healing, chronic wounds. Examples of growth factors to be mentioned are: PDGF (Platelet Derived Growth Factor), rhPDGF-BB (Becaplermin), EGF (Epidermal Growth Factor), PDECGF (Platelet Derived Endothelial Cell Growth Factor), aFGF (Acidic Fibroplast Growth Factor), bFGF (Basic Fibroplast Growth Factor), TGF xcex1 (Transforming Growth Faxtor alpha), TGF xcex2 (Transforming Growth Factor beta), KGF (Keratinocyte Growth Factor), IGF1/IGF2 (Insulin-Like Growth Factor) and TNF (Tumor Necrosis Factor).
Substantial embodiments of the wound dressing according to the invention are provided according to the features of the subdlaims, which also stipulate the active agents and auxiliary agents contained in the individual layers.
The wound dressing according to the invention will be explained in the following in greater detail by means of an embodiment example shown in FIG. 1, and the manufacture thereof will be explained by way of example.
FIG. 1 shows a section, transverse to the upper and lower sides, of the individal layers of a conventional embodiment of the wound dressing.